Therapeutically valuable 1, 2-dihyro-1, 2, 4-benzotriazine derivatives and process for preparation thereof



United States Patent Ofi 3,349,088 Patented Oct. 24, 1967 ice The present invention relates to therapeutically valuable compounds of the general formula analgetic and antipyretic properties. The compounds disclosed herein are useful for alleviating the symptoms of rheumatic and allergic diseases and symptoms such as inflammation, edema, pain, fever, and swelling of the joints, and may be administered to human patients having such symptoms in a daily dosage of 50-1200 mg.

The compounds of Formula II can be reduced by catalytic hydrogenation or by means of metals having reducing properties (Sn, Zn, Fe, etc.) or with salts of them (SnCl FeCl etc.). Reduction and isolation of the desired product is preferably carried out in an inert atmosphere such as N or H The following table shows a comparison between the compounds of this invention and the well-known anti- Xl Z1 15 rheumatics phenylbutazone and sodium salicylate, in view l; of their inhibiting efiect on the rat paw kaolin edema. 7 8 2NZ On this model all the well-known antirheumatic remedies X 6 exhibit antiphlogistic properties, even on peroral admin- 5 \f (I) istration; see Arzeimittel-Forschung 12, 1160 (1962).

' I Perorally ED (dose DL (dose DL /ED Compound N o. Substltuents of Formula given as salt b5 507 507 (theggipeut i e of acid or inhibition of letality) index) X Y Z Z base, resp. edema) NHz H H H01 145 720 5 N(CH3)2 H E H61 300 ca 1,250 ca. 4 N(CH3)2 H H 1?? ea. ca. 5 NHC H H H 00 11 5 oocnwiunoo Na+ ca. 220 ca. 800 ca.4 N(OH3)2 COCH(O4H9)CO Na+ ca. 70 440 ca. 6.3 N(CH3)2 OOCH(C4H9)CO Na+ ca. 225 3, 500 15 N(CH3)2 ooomonmoo Na+ 120 780 6. 5 rear assesses a a a 2 4 9 N(CH:)2 COCH(C3H1)OO Na+ ca. 100 1,350 Ca. 13.5

Phenylbut'i vrm e Na+ 170 770 4 Sodium salicyla NEW 600 600 2. 7

wherein X and X are identical or different members of the group consisting of hydrogen, halogen, lower alkyl, free and substituted amino groups, free, alkylated and acylated hydroxy groups; Y is a member of a group consisting of lower alkyl, aryl, free and substituted amino groups and free, alkylated and acylated hydroxy groups, and Z and Z are identical or different members of the group consisting of hydrogen and acyl radicals where both Z together may represent the diacyl biradical of a dibasic acid which may be substituted by lower alkyl, lower alkenyl, cycloalkyl, aryl and hydrocarbon radicals, eventually substituted by a member of the group including free and substituted amino radicals and free, alkylated and acylated hydroxy radicals.

The novel compounds of the invention are preferably prepared by treating a 1,2,4-benzotriazine-l-oxide of the general formula N, X I

The last column of this table shows that the therapeutic indices in the kaolin edema test for most of the compounds of this invention, are higher than those of phenylbutazone or sodium salicylate.

The following table shows that compounds of this invention on peroral administration have a higher antipyretic effect against the rat yeast fever and a stronger analgesic efiect (phenylquinone test of Siegmund) than phenylbutazone or sodium salicyl-ate.

Pheuylquinone test Yeast fever test Antipy- Analgesic effect retic elfect of a peroral EDsn (mg. kg.) dose of 250 mg./kg. sub- Compound stance tested: average decrease of temperature Oral Subcutaduring 6 hours in C.

neous 50 50 Phenylbutazone. 203 49 1. 3 Sodium salicylate-.- 580 475 2. 0

weight).

3 mgJkg.

Example 1.3-amin0-7-chl0r0-(1,2-dihydr0- 1,2,4-benzotriazine) (M0 533) 7 g. of the compound corresponding to Formula II (X=7-Cl, Y=NH are dissolved in 200 ml. 5 N

Example 2.3-dimethylamin0-(1,2-dihydro- 1,2,4-benztriazine) (M0 780) 7 g. of the compound corresponding to Formula II (X=H, Y=N(CH are, as described in Example 1, reduced with tin and hydrochloric acid. After cooling the reaction product crystallizes as a tin double salt. This salt is suspended in 50 parts of-1 N hydrochloric acid and treated at 80 C. with H 5. Evaporation of the filtered solution yields hexagonal prisms of the monochlorhydrate. M.P. 205-207 C.

C H N Cl. /2H O(221.7): Cale. C, 48.8; H, 6.33. Found C, 49.3; H, 6.3.

Example 3.3-pr0p0xy-(1,2-dihydr0-1,2,4-- benzotriazine) (M0 799) The starting material having the structure II (X=H, Y=OC3H7) can be obtained by heating 3-chloro-1,2,4- benzotriazine-l-oxide with the equivalent amount of sodium propylate in n-propanol (M.P. 90-92 C.). The hydrogenation is carried out with zinc powder and ammonia by heating a stirred mixture of 6.4 g. of the starting material with 6.4 g. of zinc powder in 260 ml. of alcohol and 130 ml. of concentrated ammonia on a water bath while introducing gaseous ammonia. As soon as the orange color of the solution disappears, the filtered alcoholic solution is evaporated under N The residue is extracted with peroxyde-free ether, and 3 N alcoholic hydrochloric acid is added to the extract. The resulting hydrochloride has a melting point of 110-111 C.

c,.,H,,N,oc1 (227.7): Cale. C, 52.73; H, 6.2; Cl, 15.57. Found C, 52.83; H, 6.36; Cl, 15.57.

Example 4 .--1 -acety l-3-prop0xy- (1 ,Z-dihydro- 1,2,4-benzotriazine) (M 0 806) 2 g. of the starting material of Formula II (X=H,,

Y. OC H are dissolved in a mixture of 20 ml. glacial acetic acid and 2 g. acetic anhydride. The reduction is.

Example 5.-7-chl0ro-3-dimethylamin0-(1,2-dih d 1,2,4-benz0triazine) (M0 817) The compound of Formula II (X=7-Cl, Y=N(CH is used as sarting material. It can be obtained from 3,7-

dichloro-l,2,4-benzotriazine-l-oxide and dimethylamine in an alcoholic solution by heating to 80 C. under pressure (M.P. 133 C.). The aforesaid starting material is treated in alcoholic solution with hydrogen in the presence of Raney nickel. The filtered solution containing the formed dihydro product is concentrated. After addition of concentrated alcoholic hydrochloric acid the product crystallizes in colorless needles of the hydrochloride. M.P. 215-220 C. (recrystallized from methanol).

c rr ci N, 247.1 Cale. c, 43.75; H, 4.89; 01, 28.69. Found C, 43.60; H, 4.89; Cl, 28.79.

Addition of an excess of alcoholic hydrochloric acid and ether to the mother liquid yields a small amount of the dihydrochloride of 7-chloro-3-dimethylamino-1,2,3,4- tetrahydro-1,2,4-benzotriazine (M.P. 203-207 C.).

C H Cl N (285.6): Cale. C, 37.85; H, 5.3; Ci, 37.25; N, 19.6. Found C, 38.22; H, 5.38; Cl, 37.20; N, 19.48.

Example 6.1,2-(n-butylmal0nyl)-3-efh0xy-7-chlor0- (1,Z-dihydro-l,2,4-benz0triazine) (M0 813') The starting material of the Formula II (X=7-Cl, Y=OC H M.P. 104.5 C., which can be obtained in a theoretical yield by reacting 3,7-dichloro-1,2,4-benzo triazine-l-oxide with sodium ethylate, is treated in alcoholic solution with catalytically activated hydrogen to give the dihydro-compound. After having evaporated the solution in vacuo, the residue is dissolved with benzene.

and the solution is dried over anhydrous CaSO To the dried solution are added 1 mol of butyl malonylchloride and 2 mols of triethylamine-both dissolved in abs. benzene. The rate of addition of the triethylarnine should be somewhat greater than the rate of the acid chloride. After standing over night at room-temperature, precipitated triethylamine chlorhydrate is filtered off on a Biichner-funnel. The product is extracted from the henzene-solution with diluted NaOH. After addition of a small excess of HCl to the alcalic solution, the product is extracted by methylene chloride. After evaporation of the solvent, a light-brown colored viscous oil is obtained. Having dissolved this oil in a small amount of alcohol, tllze5 product crystallizes in form of white needles. M.P.

C. C H ClN O (335.8): Cale. C, 57.23; H, 5.4; CI, 10.56; N, 12.51. Found C, 57.0; H, 5.54; Cl, 10.8; N, 12.49.

Example 7.] ,Z-(n-butylm alonyl -7-ch [01-0-3 -pr0 poxy- (1,Z-dihydro-I,2,4-benz0triazine) (M0 815) This product is obtained from. 7-chloro-3-propoxy- 1,2,4-benzotriazine-1-oxide (M.P. 131.5 C.) by the same method as described in Example 6. After crystallization from methanol the product melts at 107 C.

C H CIN O (349.8): Cale. C, 58.35;H, 5.76; N. 12.01. Found C, 58.15; H, 5.76; N, 12.10.

Example 8.-3-ethylamino-7-chloro-(1,2-dihydr0- 1,2,4-benzotriazine) (M0 828) per 1 mol benzotriazine-l-oxide are absorbed, the glacial acetic acid is evaporated in vacuo and the residue isdissolved in cm. ethanol. Addition of the equavalent amount alcoholic hydrochloric acid and 80 cm. ether causes the product to crystallize as a hydrochloride, which forms slightly colored needles. M.P. 193-195 C.

C9H12N4C12 Cale. C, H, N, 21.49. Found C, 46.02; H, 5.61; N, 21.49..

The free base can be liberated from the so obtained hydrochloride bytreating its aqueous solution with sodium bicarbonate followed by extraction with methylene chloride.

By analogous methods there have been synthetized the following derivatives of the 7-chloro-1,2-dihydro-1,2,4- benzotriazine substituted in the 3-position as hydrochlorides:

M.P. C.)

M0 823 the 3-piperidino derivative 203-207 M0 829 the 3-propylamino derivative 171-173 the 3-isobutylamino derivative 177-179 M0 849 the 3-(3'-morpholino) propyl derivative 223-225 M0 819 the 3-diethylamino derivative 205-209 M0 821 the 3-benzylamino derivative 180 M0 822 the 3-methylamino derivative -192 Example 9.1-acetyl-i-dimefhylamin0-7-chl0ro (1,2- dihydro-1,2,4-benzotriazine) (M0 837) 3 dimethylamino-7-chloro-1,2,4-benzotriazine-l-oxide (Formula II: X=7-Cl, Y=N(CH which has been used as starting material also in Example 5, is hydrogenated in the presence of Raney nickel in 25 volume parts of ethanol containing 20% of acetic acid. After reduction the solvent is evaporated in vacuo, and the residue is dissolved in vol. parts of glacial acetic acid. After addition of an equimolar amount of acetic acid anhydride and a few drops of cone. H 80 the solution is refluxed for half an hour. After cooling, the reaction mixture is poured onto a mixture of crushed ice and an excess of cone. NaOH solution; the precipitated product is filtered on a Biichnerfunnel. Recrystallized from methanol, the product forms lightly colored needles with a M.P. of 181-183 C.

C H CIN O (252.7): Calc. C, 52.29; H, 5.18; N, 22.17. Found C, 52.64; H, 5.15; N, 22.32.

Reaction of the same starting material as above with 2 moles of acetic acid anhydride gives the diacetyl derivative (M.P. 152 C.), with formic acid and 1 mole of acetic acid anhydride the l-formyl-derivative (M.P. 179-183 C.).

Treatment of the l-acetyl derivative with benzoyl chloride and triethylamine yields the l-acetyl-Z-benzoyl derivative (M.P. 170-171 C.), replacement of benzoyl chloride by p-chlorobenzoyl chloride affords the corresponding 1-acetyl-2-p-chlorobenzoyl derivative (M.P. 183-184 C.). By analogous hydrogenation of 3 dimethylamino 7- methyl-1,2,4-benzotriazine-1-oxide followed by reaction with ethyl-chlorcarbonate the 1,2-di(carbethoxy)-3-dimethlylamino 7 methyl (1,2-dihydr0-1,2,4-benzotri azine) is obtained (M.P. 105 C.).

Example I0.-1,Z-butflmalonyl-3-dimethylamino-(1,2- dihydro-l,2,4-benz0triazine) (M0 855) (a) In a 3'neck-flask with descending condenser to 3.8 g. of 3-dimethylarnino-(1,2-dihydro-1,2,4-benzotriazine) are added 0.52 g. metallic sodium, dissolved in a small volume of abs, alcohol, 4.5 g. of diethylbutylmalonate and ml. of xylene, in a nitrogen atmosphere. The mixture is heated during 2 hours to 70 C., then during 3 hours to 110-130 C. and during one more hour to 150 C., slowly distilling off the alcohol and most of the xylene. To the resulting lightly brown colored mass are added 200 ml. of water. The resulting solution is extracted twice with ether or benzene and afterwards acidified with HCl. Yield 3.6 g. of l,Z-butylmalonyl-3-dimethylamino-(1,2-dihydro-1,2,4-benzotriazine). After crystallisation from alcohol the melting point is 189l90 C.

(b) 3 dimethylamino-l,2,4-benzotriazine-oxide (Formula II: X=H, Y=N(CH is shaken in the presence of Raney nickel in 15 vol. parts of an alcohol-acetic acid (9:1) mixture in a hydrogen-atmosphere. The mixture absorbs 2 moles hydrogen per 1 mol starting material. Hydrogenation can also be effected using a palladium catalyst with a suitable solvent. After reduction it is filtered on a Biichner-funnel through a Hyflow-layer and the solvent is evaporated in vacuo under nitrogen. The residue is dissolved in parts of water-free dioxane and treated at 60 C. with the calculated amount of butylmalonyl chloride (1 mol/mol) and triethylamine (2 mol/mol). The separated triethylamine hydrochloride is filtered, the dioxane-solution is evaporated under vacuo to dryness, and the residue is dissolved in 7 vol. parts of boiling acetic acid. After cooling, the product separates in lightly yellowish crystals. They are dissolved in the calculated amount of 0.25 N NaOH, treated with a small amount of carbon and precipitated with HCl. Melting point of the purified product is 187 C. Yield: approximately 60% of the theoretical amount.

C H N O (300.4): Cale. C, 63.97; H, 6.71; N, 18.67. Found C, 64.08; H, 7.87; N, 18.79.

By analOgous methods the following derivatives of the 1,2 butylmalonyl 3-dirnethylamino-(1,2-dihydro-1,2,4- benzotriazine) can be prepared:

Mi 73A the 6-dimethylamino-7-chloro derivative 117-118 In an analogous manner the following 1,2-alkylmalonyl- 3-dimethylamino- 1,2-dihydro-l ,2,4benzotriazine) derivatives are obtained:

M.P. C.) M0 884 the 1,2-(propylmalonyl) derivative 207 M0 886 the 1,2-(pentylmalonyl) derivative 188 M0 887 the 1,2-(pentylmalonyl)-6-chloro derivative 200 M0 888 the 1,2-(propylmalonyl)-6-chloro derivative 195 M0 890 the 1,2-(cyclopentylmalonyl)-6-chloro derivative 191 Mi the 1,2-(propylmalonyl)-7-methyl derivative 228 Mi 88 the .1,2-(pentylmalonyl)-7-methyl deriva- 'tive 215 Example 1 2.--] ,Z-butylmalonyl-3-phenyl-(1 ,Z-dihydro- 1,2,4-benzotriazine) (M0 889B) 10 g. of 3-phenyl-1,2,4-benzotriazine (prepared according to R. Fuseo et al., 1st Lornb. r. sc., vol. 91, p. 936 (1957) C.A. 53, 9243) are dissolved in a mixture of ethanol and acetic acid and treated with hydrogen in the presence of Raney nickel. After hydrogenation the solvent is evaporated and the residue is dissolved in dioxane and in analogy to Example 10a treated with an equivalent amount of butylrnalonyl-dichloride. After evaporation of the solvent, the reaction product is dissolved in dilute sodium hydroxyde and precipitated with HCl. After recrystallisation from acetone colorless crystals are obtained with a melting point of -166 C.

We claim:

1. A chemical compound having the formula wherein X and X are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylamino;

Y is a member selected from the group consisting of amino, lower alkylamino, lower alkoxy, phenyl, piperidino, morpholino lower alkyl and phenyl lower alkyl;

Z and Z when independent groups, are independently selected from the class consisting of hydrogen, acyl radicals of lower aliphatic carboxyl acids, and acyl radicals of araliphatic carboxylic acids;

Z and Z when linked together, represent the diacyl di-radical of an acid selected from the group consisting of lower aliphatic dibasic carboxylic acids and lower aliphatic dibasic carboxylic acid whose alkylene group is substituted with cycloalkyl;

and when Y is amino, at least one of X X Z and Z is not hydrogen.

2. A chemical compound according to claim 1, wherein at least one of Z and Z is not hydrogen.

3. The 3-ethylamino-7-chloro-1,2-dihydro-1,2,4-benzotriazine.

4. The 1,2 propylmalonyl-3-dimethylamino-6-chloro- 1,2-dihydro-1,2,4-benzotriazine.

5. The 1,2-propylmalonyl-3-dimethylamino-7-methyl-1 2-dihydro-1,2,4 benzotriazine.

6. The method of producing a compound having the formula wherein X and X are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylarnino;

Y is a member selected from the group consisting of amino, lower alkylamino, lower alkoXy, phenyl, piperidino, morpholino lower alkyl and phenyl lower alkyl;

Z and Z when independent groups, are independently selected from the class consisting of hydrogen, acyl radicals of lower aliphatic carboxylic acids, and acyl radicals of araliphatic carboxylic acids;

Z and Z when linked together, represent the diacyl dis-radical of an acid selected from the group consisting of lower aliphatic dibasic carboxylic acids and lower aliphatic dibasic carboxylic acids whose alkylene group is substituted with cycloalkyl;

which comprises. treating a 1,2,4-benztriazine-1-0xide having the structure a X1 s X2 l LY wherein X X and Y have the meaning given above, with a hydrogenating agent and isolating the thus obtained product as a salt or an acyl derivative.

7. The method according to claim 6 which comprises acylating the hydrogenated product by introducing into 1,2-position the diacyl biradical of a dicarboxylic acid.

8; The method according to claim 6 which comprises acylating the hydrogenated product by introducing in o 1,2-position the diacyl biradical of a dicarboxylic acid having the formula wherein R and R are independently selected from the class consisting of hydrogen, lower alkyl and cycloalkyl.

References Cited UNITED STATES PATENTS 2,489,353 11/1949 Wolf 260-248 

1. A CHEMICAL COMPOUND HAVING THE FORMULA 